Vascular disease is the most common cause of morbidity and mortality in the western world, surpassing any other single degenerative disease. The fundamental pathology of vascular disease is an abnormal accumulation of cells within the subintimal space below the surface of the endothelial cell lining, resulting in a decrease in lumen size and tissue perfusion. This accumulation is due to the proliferation and/or migration of smooth muscle cells, and/or inflammatory cells into the intimal layer of a vessel, resulting in restricted blood flow through that vessel, i.e. neointimal occlusive lesions.
Current efforts aimed at preventing and treating vascular disease are directed at developing improved lipid-lowering agents (e.g., for treatment of atherosclerosis) and immunosuppressive regimens. For example, lipid lowering agents are currently used in the treatment of atherosclerosis. Alternatively, immunosuppressive regimes are used in allotransplantation for prevention of transplant-associated vasculopathy (TAV), also referred to as transplant arteriosclerosis. TAV is closely related to atherosclerosis and remains the major barrier to successful transplantation (Brooks-Wilson et al., Nature Genetics, (1999) 22:327-335; Kirk et al., Nature Medicine (1999) pages 686-693; Hancock et al., Nature Medicine, (1998) 4:1392-1396). Alternatively, surgical strategies have been developed that are aimed at bypassing the obstruction with venous conduits, or stretching the vessel to create a larger lumen by performing balloon angioplasty.
Despite the substantial benefit attributable to the use of current cholesterol lowering and immunosuppressive drug therapies, these treatments do not achieve an acute reduction in vascular lesion size. Furthermore, bypass surgery may accelerate progressive lesion stenosis, and interventions such as balloon angioplasty often result in the development of restenosis. There exists the need of a strategy for preventing and treating vascular disease.
The role of the protein A20 has been studied extensively in endothelial cells and suggests that A20 plays an anti-apoptotic role in response to inflammatory stimulus.